December 2012 – RSC Medicinal Chemistry Blog

Archive for December, 2012

Themed Issue Highlighting New Talent In Medicinal Chemistry Now Published

21 Dec 2012

Welcome to the first issue of MedChemComm of 2013. Join us in taking a look at our successes from the last year and in looking forward to another exciting year for the journal by reading our New Year Editorial.

Not only is this issue the first of a new year it is also our New Talent themed issue, where we showcase the strength of research being carried out by some of tomorrow’s leaders in the field with 36 high quality articles.

This stunning cover (right) highlights the work of Seung Bum Park et al. who have discovered a novel heterobiaryl pyrazolopyridine skeleton as a selective FLT3 inhibitor from phenotype-based viability profiling and hypothesis-driven deconvolution.

Discovery of a highly selective FLT3 kinase inhibitor from phenotypic cell viability profiling
Sanghee Lee, Ala Jo and Seung Bum Park
DOI: 10.1039/C2MD20169K

Stars, stars everywhere, and it’s not just the rising stars featured in this issue that we’re talking about with this cover (left) from Stephen P. Andrews and Benjamin Tehan. Andrews & Tehan review the first example of structure-based drug design with G protein-coupled receptors (GPCRs) thanks to StaR® proteins (stabilised GPCRs), and how this has enabled the identification of a preclinical candidate for the treatment of Parkinson’s disease.

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A_2A receptor
Stephen P. Andrews and Benjamin Tehan
DOI: 10.1039/C2MD20164J

Read it all today by visiting our journal home page.

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Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

20 Dec 2012

This review from the MedChemComm New Talent themed issue covers one of the first successful examples of structure-based drug design for stabilised G protein-coupled receptors (GPCRs), focusing on the development of a pre-clinical candidate for the treatment of Parkinson’s disease using StaR® technology.

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A_2A receptor
Stephen P. Andrews and Benjamin Tehan
DOI: 10.1039/C2MD20164J

Stephen P. Andrews and Benjamin Tehan from Heptares Therapeutics Limited review the role the application of StaR® proteins plays in the discovery and development of new ligands for the adenosine A_2A receptor (A_2AR).

StaR® proteins are GPCRs which have had a small number of point mutations introduced to thermostabilise them. These proteins are stable in detergent micelles and are suitable reagents for use with X-ray crystallography, biophysical screening
techniques and fragment screening. These properties have enabled the application of biophysical screening techniques of ligand–receptor complexes and have facilitated their crystallisation, which has allowed true structure-based drug design on a GPCR to take place for the first time.

This review is separated into two main parts:

1) Applications of stabilised GPCRs
– Describing the thermostabilisation process for generating StaR® proteins and, using A_2AR as an example, considers the implications that this has on receptor conformation.

2) Structure-based drug design with StaRs®
– Discussing how the application of techniques covered in the first part of the review aided in the optimisation of a hit A2AR antagonist which was identified by virtual screening of experimentally enabled homology models.

Read the complete review here…

and find more articles from our New Talent themed issue here…

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MedChemComm prizes at 6th Biological and Medicinal Chemistry Symposium

18 Dec 2012

Congratulations to Mark Rackham and Kerya Long, winners of the MedChemComm prizes at the 6^th Biological and Medicinal Chemistry Symposium.

Mark, who is part of Professor Robin Leatherbarrow’s group at Imperial College, London, received the prize for Best Oral Contribution for his presentation entitled ‘Design and Synthesis of Highly Potent Inhibitors of Plasmodium falciparum N-Myristoyltranferase as a promising treatment for malaria’.

Oral contribution prize winner Mark Rackham with BMCS Committee member Dave Alker

Kerya, from Dr Andrew Wilson’s group at University of Leeds, was awarded Best Poster Contribution for ‘Development of synthetic α-helix mimetics as potent anticancer agents’. Both winners receive a year’s subscription to MedChemComm.

Poster contribution winner Kerya Long with Dave Alker

The symposium, organised by the RSC’s Biological & Medicinal Chemistry interest group, was held at the University of Cambridge on 14^th December 2012.

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Helping the fight against flu

18 Dec 2012

With up to five million cases of the acute respiratory illness influenza leading to half a million deaths each year worldwide, the search for better treatments is important. Scientists from Australia and the US have developed a synthesis for a drug that gives higher yields and antiviral activity than currently used commercial drugs, such as Relenza (zanamivir) and Tamiflu (oseltamivir), they claim.

Although existing dimeric zanamivir compounds show significant therapeutic potential, the currently used synthesis method only produces the compounds in moderate yields. Benjamin Fraser and co-workers at the Australian Nuclear Science and Technology Organisation have designed a higher-yielding synthesis route, which can also prepare the dimers with new linker functionality.

The group prepared the new class of zanamivir dimers by using a known cycloaddition reaction that improved the coupling yields and allowed rapid optimisation of the antiviral activity as a function of the linker length. The dimers synthesised are among the most effective inhibitors of influenza to date, being up to 3000 times more potent than zanamivir. This potency may be because the dimers work by a dual mechanism: they inhibit neuraminidase (an enzyme on the virus’ surface and a target in influenza treatments) and their aggregation is enhanced.

Although vaccination programs reduce the risk of an epidemic influenza outbreak, there is still a need for antiviral drugs © Shutterstock

Fraser comments that the dimers are still at the research stage, so a significant amount of further testing is required before the drugs can be ready for human use. The group hopes to radiolabel the compounds in the future so the bio-distribution, metabolism and retention time in the lungs can be measured. Fraser also mentions that it may also be possible to obtain even greater antiviral activity by developing high order multimers, including trimers and tetramers of zanamivir, as each neuraminidase receptor on the virus has four active sites.

Although neither approach used by the group is new, comments Hans Streicher at the University of Sussex, UK, the study adds ‘valuable information regarding the optimal distance’ between the inhibitor moieties, and will thus aid the development of a new generation of anti-influenza drugs.

Story first published in Chemistry World

And read the full MedChemComm paper for free for 4 weeks here:

Synthesis of 1,4-triazole linked zanamivir dimers as highly potent inhibitors of influenza A and B
Benjamin H. Fraser, Stephanie Hamilton, Anwen M. Krause-Heuer, Philip J. Wright, Ivan Greguric, Simon P. Tucker, Alistair G. Draffan, Valery V. Fokin and K. Barry Sharpless

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Challenges in Chemical Biology (ISACS11) – Call for Abstracts

14 Dec 2012

We are proud to announce that the significant International Symposia on Advancing the Chemical Sciences (ISACS) series will return in 2013 to include Challenges in Chemical Biology (ISACS11) on 23-26 July 2013 in Boston, UK.

Abstracts are now invited for this event so submit today and take advantage of this exceptional opportunity to present your work alongside scientists from across the globe.

For details of speakers and conferences themes, please visit the dedicated website.

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RSC Medicinal Chemistry Blog

Archive for December, 2012

Themed Issue Highlighting New Talent In Medicinal Chemistry Now Published

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

MedChemComm prizes at 6th Biological and Medicinal Chemistry Symposium

Helping the fight against flu

Challenges in Chemical Biology (ISACS11) – Call for Abstracts

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